Complement Expression in Alzheimer's Disease Brain. This project addresses the role of the complement (C) system, a major cytotoxic arm of the immune system, in degenerative and regenerative processes in the brain. Recent immunohistochemical evidence demonstrates activated C components associated with senile plaques, dystrophic neurites and neurofibrillary tangles in AD brain. We found several C component mRNAs up-regulated in AD brain, including SGP-2/CLI, an inhibitor of the C5b-9 membrane attack complex. Our evidence also shows up-regulation of C1q and C4 and SGP-2/CLI mRNAs in afferent target sites after deafferenting lesions of rat brain. These results suggest involvement of the complement system in Alzheimer pathology and brain injury response. Study 1 identifies the C expressing brain cell types and determine whether C expression correlates with AD brain pathology. Comparison with rodent brain lesions addresses the hypothesis that C has a role in AD neurodegeneration. Study 2 uses afferent transection and peripheral kainate brain lesion models to investigate C in cell death and synaptic remodeling processes in hippocampus. Afferent transection lesions produce neurodegeneration and reactive synaptogenesis in distinct sites, allowing examination of both processes in the same animal. Study 3 investigates the in vivo effect on C gene expression of amyloid beta/A4 peptide/purified AD amyloid injection into rat brain. We will test the hypothesis that amyloid can activate C (induce C mRNAs, stimulate MAC production and attract inflammatory cells) and promote neurotoxicity. Study 4 determines whether responses of the complement system to afferent pathway transection and b-amyloid peptide/fibril injection vary with the age of the animal. Aged humans have elevated serum C which may impinge upon ability of brain to respond to neurodegeneration.